Preparation of 3-oxo-19-nor-{66 {hu 4{b -steroids from 10-{8 3-substituted-alkyl{9 -desasteroids

ABSTRACT

An improved process for converting 10-(3-substituted-alkyl)-19nor-desA-steroids to pharmaceutically valuable 3-oxo- Delta 4-19nor steroids via oxime and hydrazine derivatives is described. The end-products are a known class of steroids which are useful as hormonal agents.

O United States Patent 1 m1 Rosenberger et al. Dec. 23, 1975 PREPARATIONOF 3-OXO-l9-NOR-N-STEROIDS FROM [56] References Cited MUSUBSMBALKYLI'FOREIGN PATENTS OR APPLICATIONS DESAsrERomS 7,001,893 1970 South Africa[75] Inventors: Michael Rosenberger, Caldwell;

Gabriel saucy, Essex Fellsboth of Primary Examiner-Gerald A. SchwartzAttorney, Agent, or Firm-Samuel L. Welt; Jon S. [73 Assignee:Hoffniann-La Roche Inc., Nutley. Saxe; Raymond wmekmd NJ. 221 Filed:Apr. 11, 1974 [57] d :BSTRACT lo b d An improve process or converting-su stitute [21] Appl' 459379 alkyll-l9-nor-desAstJeroids topharmaceutically valuable 3-oxo-A- l9-n0r steroids via oxime andhydrazine 52 US. Cl. 260/566 AE; 260/469; 260/490; derivatives isdescribed The end-Products are a 260/566 R; 260/566 A; 260/566 13 knownclass of steroids which are useful as hormonal [SI] Int. C07C 131/02agems- [58] Field of Search 260/566 A, 566 R, 566 AB, 8 Claims, NoDrawings PREPARATION OF 3-OXO-l9-NOR-N-STEROIDS FROMIO-[S-SUBSTITUTED-ALKYL]-DESASTEROII)S RELATED APPLICATIONS The presentapplication is based upon co-pending application, Ser. No. 17,964, filedMar. 9, 1970, which is a continuation-in-part of Ser. No. 813,693, filedApr. 4, 1969, now abandoned, the benefit of the filing date of which ishereby claimed.

BACKGROUND OF THE INVENTION In recent years much effort has been devotedto the total synthesis of steroids. On such synthesis is the approachdisclosed and claimed in U.S. Patent of Gabriel Saucy, Pat. No.3,544,598 and abandoned US. Patent applications, Ser. Nos. 633,730,filed Apr. 26, 1967, 604,124, filed Dec. 23, 1966 and 549,816, filed May13, 1966. Briefly, the Saucy approach comprises reacting a7-substituted3-oxo-1-heptene or variant thereof with2-alkyl-cycloalkane-l,3-dione yielding a3-substituted-6a-fi-alky1-cyclopenta[f][llbenzopyran or naphtho[2,1-b]pyran. The latter compounds are then subjected to a selectivecatalytic hydrogenation followed by the introduction of a hydroxy,alkoxy or acyloxy group at the 4a-position to produce a3-substituted-6aB,4a-hydroxy, alkoxy or acyloxyperhydrocyclopenta[f][1]benzopyran or perhydronaptho [2,1-b] pyran. Bymeans of one of the alternative approaches disclosed therein, thesepyrans are then converted to 10-[ 3-substituted-alkyl1-l 9-nor-desA-steroids (hereinafter represented by Formula I) which in turn areconverted to known pharmaceutically valuable steroidal materials.

This invention provides an alternative route to that which is disclosedin the prior Saucy applications referenced above for convertinglO-[3-substituted-alkyl1- 19-nor-desA-steroids to known pharmaceuticallyvaluable 19-n0r steroids. By the methods of the present invention, oneis able to obtain valuable steroid endproducts is extremely high yields.The 3-keto-Al 9-norsteroid end products are a known class of compoundshaving hormonal activity, particularly anabolic/androgenic,progestational and antiestrogenic activity. Additionally, thesecompounds are readily convertible by A-ring armatization to steroids ofthe estrane series having, for the most part, estrogenic activity. Acompilation of many of the l9-norsteroids obtainable by the presentprocess, as well as a discussion of the biological properties, may befound in Applezweig, Steroid Drugs", McGraw Hill, 1962. Additionalleading references to this class of compounds are:

Colton, et al, J.A.C.S., 79, 1123 (1957);

U.S. Pat. 3,442,918;

U.S. Pat. 2,712,871;

U.S. Pat. 3,427,389; and

U.S. Pat. 2,744,122.

A compilation of A-ring aromatizations of l9-norsteroids may be found inDjerassi, Steroid Reactions", Holden-Day, 1963, Chapter 9, Section 5.One particularly valuable steroid end-product obtained by the methodsdisclosed herein is norgestrel(l3f3-ethyl-l7aethynyl-17-hydroxy-gon-4-ene-3-one). Preparation of thiscompound requires the introduction of an a-ethynyl group in the C-1 7position at some convenient stage in the process. The introduction ofthe ethynyl group into the steroid nucleus in high yields is a delicatestep which is often associated with subsequent loss of this group inlater process steps in the synthesis. Preparation of the l7a-ethynylderivatives is greatly faciliated by the process of the instantinvention in that the grouping can be introduced several stages beforethe conclusion of the synthesis without subsequent loss thereof. This isso since the ethynyl group is stable to the'process conditions employedherein. Moreover, by-product formation has been substantially reduced inaccordance with the teachings of the subject invention therebyfacilitating separating and purification procedures. Elimination ofby-product formation also contributes to the obtention of highend-product yields.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates tocertain novel polycyclic compounds and processes for their synthesis.More particularly, the novel intermediates and processes of thisinvention provide a new synthetic route for the preparation of knownpharmaceutically valuable 3- oxo l 9-nor-A-steroids.

In one aspect, this invention is directed to a process for preparing3-oxo-l9-nor-N-steroids from l0-[3-substituted-alkyl]desA-steroids ofthe partial formula:

I 15 R 2 1 4 M a j I. 5 R CH2-R wherein M represents the remaining ringsof the steroid nucleus, i.e., the D ring; R and R are each independentlyhydrogen or lower alkyl; R or OR; R is hydrogen; R is monocycliccarbocyclic aryl-lower alkyl, hydrogen, acyl or a radical of the formulawherein each of R, R and R when taken alone is independently loweralkyl; R is hydrogen or lower alkyl, and R is lower primary alkylcontaining from 1 to 5 carbons.

The invention sought to be patented in its process aspect is containedin the following flow diagrams, captioned Reaction Scheme A and ReactionScheme B, which schematically detail the preparation of 3-oxol 9-nor-N-steroids represented by the Formula V1 (Reaction Scheme B) from10-[3-substituted-alkyll-desA- steroids represented by Formula I(Reaction Scheme A). Only the partial formulas are shown since theremainder of the structure does not enter into the reaction. Theinventive steps include steps (e), (f), (g), (h) and (i).

REACTlON SCHEME B (See Reaction Scheme 83 CH2 M I l H i ll l R15 (2) R5(5) is n 1 In Reaction Schemes A and B, R", R, R, R, R and branchedchain saturated hydrocarbyl group contain- M are defined as aforesaid; Ris lower alkoxy, hydroxy ing from 1 to 7 carbon atoms, inclusive, andincludes or a radical of the formula methyl, ethyl, isopropyl, butyl andthe like. The term primary alkyl group denotes an alkyl group having its/X valence bond from a carbon bonded to at least two hydrogens. The termmonocyclic carbocyclic aryl de- Y notes a phenyl or substituted phenylgroup. Substituted phenyl radicals have one or more than one of the samewherein X and Y are each independently lower alkyl', or differentsubstituents attached to any position avail- M represents the remainderof the steroid nucleus, i.e., able for substitution. Substituents on thearyl group are, the B, C and D rings; and R is primary lower alkyl forexample, lower alkyl, e.g., methyl, ethyl and the having from I to 5carbons. like, etherified hydroxyl, such as, lower alkoxy, e.g.,

As used throughout the specification and appended methoxy, ethoxy, andthe like. The term monocyclic claims, the term lower alkyl denotes astraight or carbocyclic aryl-lower alkyl comprehends, for example,phenyl-lower alkyl, e.g., benzyl, l-phenylethyl, 2-phenylethyl and thelike. The term hydrocarbyl groups denotes a monovalent substituentconsisting solely of carbon and hydrogen. The term hydrocarbylenedenotes a divalent substituent consisting solely of carbon and hydrogenand having its valence bonds from different carbons. The term aliphaticwith reference to hydrocarbyl or hydrocarbylene denotes groupscontaining no aromatic unsaturation, but which can be otherwisesaturated or unsaturated, i.e., an alkylene or alkyl, or an aliphaticgroup containing olefinic or acetylenic unsaturation. The term acylgroup denotes a group consisting of the residue of a hydrocarbylcarboxylic acid of up to 20 carbon atoms exemplified by the loweralkanoic acids, e.g., acetic, propionic, butyric; the monocyclic arylcarboxylic acids, e.g., benzoic and toluic acid, formed by removal ofthehydroxyl portion of the carboxyl group.

The 3-oxo-l9-nor-A -steroids of Formula VI which can be prepared inaccordance with Reaction Schemes A and B above have been only partiallyrepresented therein since the remainder of the molecular structureeither does not enter into the reaction or is transformed and thenreturned to its original structure during the reaction sequence. It willbe appreciated that the unadorned molecular structure represented by Mand M as defined aforesaid can bear groups elsewhere in the nucleusuneffected by process conditions, such as, for example, not beinglimited thereof, at C-l3, primary alkyl groups, such as methyl, ethyl orpropyl; at C-l 7a, i.e., alkyl groups, such as, methyl, ethyl, or propylor at C-l 75, alkoxy groups such as methoxy or ethoxy, or an ester ofhydrocarbon carboxylic acid having up to 8 carbons, such as acetoxy,propionyloxy or benzoyloxy carbonyl. It should be noted that groupscontaining unsaturation such as at C-l7a, i.e., alkenyl groups such as,vinyl and allyl; and alkynyl groups, such as, ethynyl and propargyl,should not be inserted in the indicated at a point in the reactionsequence prior to a catalytic hydrogenation step. Furthermore, if asecondary hydroxy group is desired at 0173, then suitable protectinggroups, such as alkoxy or ester groups should be provided during theaforesaid reaction sequence, which protective groups may be removedduring the last step of the sequence in a manner known per se.Additionally, an oxo group at C-l7 may be transformed into a nitrogenderivative during the course of the reaction and then regenerated priorto the end of the sequence.

The processes of the present invention will now be generally describedso as to enable one skilled in the art to practice the invention.

The l-[3-substituted-alkyl]-A"' starting reactants represented by thepartial Formula I in Reaction Scheme A may be obtained according toprocedures described hereinafter and in US. Pat. 3,544,598, andabandoned US. Patent applications Ser. No. 633,730, filed Apr. 26, I967and 633,693, filed Apr. 26, I967. The tricyclic compounds represented byFormula I can be named either as derivatives of benz[e]indenes or asdesA-steroids and both designations are employed herein.

The enol-ethers represented by the Formula II can be obtained bysequential routes (a) and (c) of Reaction Scheme A. Thel0-[3-substituted-alkyl]-A"-desA- steroids of Formula I are firsthydrogenated in accordance with step (a) of Reaction Scheme A to yieldthe 3-oxo-saturated compounds of Formula VII. The hydrogenation issuitably conducted using a noble metal catalyst, such as, palladium,platinum or rhodium, with the preferred catalyst being palladium. Thesecatalysts can be employed in the form of the metal alone or can bedeposited on suitable support material, with carbon being preferred. Thehydrogenation is conducted in the presence of a tri-lower alkyl amine,such as, triethylamine in an inert organic solvent such as ahydrocarbon, e.g., toluene, benzene; or lower alcohol, such as methanolor ethanol. The hydrogenation can be conducted under ambient conditions,i.e., atmospheric pressure and room temperature, although theseconditions are not critical and higher or lower temperatures andpressures can also be suitably employed.

The enol-ethers of Formula II can be obtained from the 3-oxo-saturatedcompounds of Formula VII in accordance with step (c) of Reaction SchemeA by cyclizing the latter compounds. The cyclization may be effected byheating the 3-oxo-saturated compounds of Formula VII to a temperature ofbetween 50C. and 150C., preferably at a temperature range of C. to C.The cyclization is conducted in the presence of a mineral or organicacid catalyst. An organic acid such as aryl sulfonic acid, e.g.,p-toluene sulfonic acid is preferred.

Alternatively, the enol-ethers of Formula II can be obtained viasequential process routes (b) (d). Thus, the l0-[3-substituted-alkyl]-A-desA-steroids of Formula I are cyclized in accordance with step (b) ofReaction Scheme A to yield the novel 4-oxa-A compounds of Formula VIII.The cyclization is suitably effected by the application of heat in thepresence of a mineral acid, such as sulfuric acid or hydrogen halides,e.g., hydrochloric acid; or an organic acid, preferably an aryl sulfonicacid such as benzene-sulfonic acid or p-toluene sulfonic acid. Thecyclization reaction can be conducted in any suitable inert organicsolvent, preferably however, a hydrocarbon, such as, benzene or tolueneis employed. The reaction is conveniently carried out at the refluxtemperature of the solvent although lower reaction temperatures can alsobe employed consistent with carrying out the reaction in a minimum oftime without undue difficulty. When the l0-[3-substituted-alkyl]-A"-desA-steroid of Formula I is defined so that R is hydrogen and R is ORwherein R is hydrogen, the cyclization can be effected by theapplication of heat alone, the above indicated acids or a combination ofboth.

The enol-ethers of Formula II can be obtained by a novel selectivehydrogenation of the dienes represented by Formula VIII in accordancewith step (d) of Reaction Scheme A. The hydrogenation can be suitablyeffected by employing a noble metal catalyst such as, palladium,platinum and rhodium with the preferred catalyst being palladium. It ispreferred to deposit the catalyst on a suitable support material, carbonbeing found to be most convenient for the purpose. The hydrogenation issuitably conducted in the presence of an inert organic solvent,preferably, a hydrocarbon such as benzene or toluene. Ambient conditionsof room temperature and atmospheric pressure are generally preferred toavoid significant hydrogenation of the A bond. The hydrogenation must beeffected under basic conditions. A most suitable base has been found tobe a tri-lower alkylamine, such as, triethylamine.

It is presumed that any of the substituents which may be present on theunadorned molecular structure as previously defined are already present.However, it will be appreciated that certain of these substituents neednot be present and can be conveniently introduced into the steroidnucleus at a convenient point in the process. It has been foundparticularly convenient to introduce at the C-l 7 position at this stagein the process alkynyl groups, particularly the ethynyl group when suchsteroid is the desired end-product. The enol-ethers represented byFormula ll wherein the C-l7 position is carbonyl, can be alkynylatedwith a suitable organo-metallic acetylide. Exemplary of the suitablealkynylating agents to effect the C-l'l substitution are alkaliacetylides, such as, lithium acetylide, potassium acetylide, sodiumacetylide and the like. The reaction is carried out in liquid ammonia ina suitable solvent system, such as, for example, an ether, e.g.,tetrahydrofuran or a hydrocarbon, e.g., toluene. The reaction isconveniently effected at the reflux temperature of the reac tion mediumalthough temperatures of between 60 to 30C. are suitable.

Other substituents if not already present on the starting steroidnucleus can be introduced by methods known to those skilled in the art.For example, C-l7 alkyl substituent can be introduced by alkylationagents, such as, for example, Grignard reagents or metal alkyls by knownmeans.

A significant aspect of the instant invention lies in the conversion ofthe enol-ethers represented by Formula ll to the 3-oxo-l9-nor-A-steroids represented by the Formula VI in accordance with process steps(e) (f) (g) (h) or alternatively via process steps (e)- (f) (i) asdepicted in Reaction Scheme B. In this process aspect, the invention canbe generally described as residing in the concept of trapping thepotential carbonyl function of the enol-ether represented by Formula [Ias a nitrogen derivative represented by the radical =NR wherein R isdefined as aforesaid.

The nitrogen derivatives represented by Formula [ll can be obtained inaccordance with step (e) of Reaction Scheme B from the enol-ethersrepresented by the Formula II by treating the later compounds with areagent of the formula wherein R is defined as aforesaid.

It has been found preferable to carry out the conversion to the nitrogenderivatives of Formula lll [step (e)] wherein the nitrogen reagent ofFormula IX, in the form of its corresponding inorganic or organic acidaddition salt is employed. Suitably, the salt may be formed with aninorganic mineral acid, especially from sulfuric acid or a hydrohalicacid, e.g., hydrochloric, hydrobromic or hydroiodic acid or an organicacid such as an aliphatic organic acid, e.g., lower alkanoic acids suchas acetic acid, propionic acid or oxalic acid, or aryl carboxylic acids,e.g., benzoic acid. In general, any acid strong enough to form theaddition salt can be used.

Preferred agents of the Formula [X are those wherein R is lower alkoxy,especially methoxy.

The conversion of the enol-ethers of Formula II to the hydroxy-nitrogenderivatives represented by Formula Ill is suitably conducted by treatingthe enol-ether with the nitrogen reagent represented by Formula IX in asuitable inert organic solvent, such as, pyridine; dimethylformamide; anether, e.g., tetrahydrofuran or dioxane; or a lower secondary alkanol,e.g., isopropano]. By inert organic solvent as employed herein is meantan organic solvent which dissolves the reactants but will not interactor interfere with their action.

Other equally suitable solvents than those exemplified immediatelyheretofore will readily suggest themselves to those skilled in the art.The reaction can be suitably carried out within a temperature range of0C. to 60C. However, for convenience room temperature is preferred. Thereaction times and temperatures employed are not critical and simplyrepresent convenient conditions consistent with carrying out thereaction in a minimum of time without undue difficulty.

When the reagent of Formula IX is employed as its salt, the reactionmust be carried out in the presence of base. Exemplary of the baseswhich can be used are pyridine, tri-lower alkyl amines, e.g.,triethylamine; alkali metal salts derived from organic carboxylic acids,e.g., sodium acetate or alkali metal hydroxide, e.g., sodium hydroxideand the like.

The oxo-nitrogen derivatives of Formula IV can be obtained by oxidizingthe hydroxy-nitrogen compounds represented by Formula [II in accordancewith step (f) of Reaction Scheme B. In general, the oxidation reactioncan be effected by any suitable oxidizing agent. As the oxidizingreagent or method, there can be utilized chromic acid in acetone; theOppenhauer oxidation, e.g., metallic alkoxide, cf. R.V. Oppenhauer, Rec.trav. Chem. 56, B7 (1937) or silver carbonate in refluxing hydrocarbonsuch as xylene.

However, it should be noted in those cases wherein the oxo-nitrogenderivative of Formula IV contains a substituent which is not inert tothe oxidizing agent, special conditions must be employed. Thus, when theC-l7 position contains, for example, an unsaturated moiety, e.g., analkynyl group such as the ethynyl group, the reaction must be effectedunder very mild oxidizing conditions. One suitable mild oxidizing methodwhich has been found to be particularly convenient is the Snatzkemethod, which is fully described in Chem Ber., 94, 729 (i961). Briefly,in the Snatzke method, a chromium trioxide-sulfuric acid reagent in adimethylformamide solvent is employed. It has been found that superiorresults can be achieved when adapting the Snatzke oxidation to theinstant invention by modifying the conditions employed therein.Specifically, it has been found desirable to use twice the amount ofacid that Snatzke specifies. The oxidation reaction using this reagentcan be conducted at a temperature range of from about l0 to about +40C.However, it has been found especially advantageous to conduct thereaction within a temperature range of from about 0C. to about 25C.Conveniently the reaction can be carried out using any inert organicsolvent although N,N-di-lower alkyl-lower alkanoyl amides such asdimethylformamide or dimethylacetamide have been found to beparticularly convenient.

The diketo compounds represented by Formula V may be obtained from theketo-nitrogen derivatives of Formula IV in accordance with step (g) ofReaction Scheme B by hydrolysis exchange. Suitably, the reaction can becarried out using a reaction partner containing reactive carbonedfunctions such as dialkylketones, e.g., acetone; or an organic keto-acidsuch as pyruvic acid or levulinic acid. The reaction is conducted in thepresence of a mineral acid, such as sulfuric acid or hydrohalic acid,e.g., hydrochloric acid at a temperature range of from about 0C. to 50C.It has been found convenient, however, to carry out the reaction at roomtemperature. Any inert organic solvent suitable for the conversion maybe employed. Exemplary are hydrocarbons, e.g., toluene or chlorinated3,928,446 ll 12 hydrocarbon, e.g., chloroform. Nitrogen derivatives ofcially aryl sulfonic acids such as p-toluene sulfonic the C-l7 oxogroup, if present, will also be converted acid. back to the x0 moietyunder the aforesaid conditions, I In another aspect, this inventioncomprehends cer- The desired 3-oxo-l9-nor-A end-product steroids tain ofthe novel compound which are partially reprerepresented by Formula Vlcan be obtained by cycliz- 5 sented in Reaction Schemes A and B. Thesecoming the diketo compounds of Formula V in accordance pounds can be'more completely represented by the with step (h) of Reaction Scheme B.The cyclization stru tural formula shown below:

can be effected under either basic or acidic conditions wherein Z iscarbonyl, C=NR or a group of the by means known to the art. The basiccyclization can formula be effected with dilute alkali hydroxide, e.g.,potassium hydroxide or sodium hydroxide, which has been found 1 to beparticularly convenient. Exemplary of the useful B acids which may beemployed to effect the cyclization are inorganic mineral acids,especially hydrohalic acids, e.g., hydrochloric, hydrobromic and thelike or 1 is hydrogen or lower acy]; 8 is hydrogen or lower an organicacid such as, a lower alkanoic or aryl caraliphatic hydrocarby]; T iscarbony| or boxylic acid, especially substituted aryl sulfonic acids,

such as, benzene sulfonic acid or p-toluene sulfonic acid. The reactioncan be suitably conducted at a tem- \C/ perature range of from to thereflux temperature of the solvent with the latter conditions beingpreferred.

The reaction can be carried out in any suitable inert organic solventwith a hydrocarbon, such as, benzene, 40 m is an integer having a valueof from l or 2; and R,

toluene or xylene being preferred. R, R R, and R are defined asaforesaid.

Alternatively, the keto-nitrogen derivatives of For- As is apparent, theabove formulas are derived from mula IV can be directly converted to3-oxo-l9-nor-A- Reaction Schemes A and B wherein M is a preferredsteroids represented by Formula VI in accordance with moiety of thepartial formula r or and M is a preferred moiety of the partial formulastep (i) of Reaction Scheme B. The direct conversion comprises an acidcatalyzed hydrolysis and cyclization. it is effected using an aqueousorganic or mineral acid in an inert water miscible organic solvent,preferably m.

lower alcohol, e.g., methanol; or tetrahydrofuran or dioxane. Thereaction is conveniently accomplished at wherein Z, Z, m and R aredefined as aforesaid. the reflux temperature of the solvent although thetem- Further preferred compounds are those wherein R perature of thereaction is not critical and temperatures and R are hydrogen; R ishydrogen; R is hydrogen; below reflux can be suitably employedconsistent with R" iS carrying out the reaction in a minimum of timewithout undue difficulty. Exemplary of the mineral acids are m sulfuricacid or a hydrohalic acid, e.g., hydrochloric acid; exemplary of theorganic acids are lower alkanoic acids, e.g., acetic acid or arylcarboxyhc acids espe- R" 13 wherein each R R and R is lower alkyl,especially methyl; R is lower alkoxy, especially methoxy; m is l and Zis carbonyl or wherein R is hydrogen; R" is lower hydrocarbyl,especially lower alkynyl and R is methyl, ethyl or propyl.

Exemplary of the compounds of formula Xl are 6-[3-oxo-butyl]-3a,B-ethyl-7-methoxyimino-3a-ethynyl-3-hydroxy-perhydro[3H]benz[e]indane;6-[3-oxobutyl]-3a,B-methyl-3,7-dimethylimino-perhydro-[3H1-benz[e]indane;6-(3-hydroxybutyl)-3a,B-ethyl-3aethynyl-3fi-hydroxyperhydro-l3H]benz[e]indan-7-one-N,N-dimethylhydrazone; 6-(3-hydroxybutyl)-3a,B-methyl-3,7-dimethoxyimino-perhydrol3H- ]benz[e]indane;6-(3-hydroxybutyl)-3a,B-ethyl-3,7- dimethoxyimino-[3H]benz[e]indane,6-(3-oxo-butyl)- 3a,B-methyl3,7-dimethoxyimino-perhydro-[3H]benz[e]indane.

The l0-[3-substituted-alkyl]-A starting reactants represented by thepartial Formula I in Reaction Scheme A may be obtained according to theproce dures escribed in US. Pat. 3,544,598, and abandoned patentapplication Ser. No. 633,693, filed Apr. 26, I967; and Ser. No. 604,124,filed Dec. 23, 1966. The derivatives of Formula I not specificallyexemplified therein may be obtained by methods available to thoseskilled in the art. For example, the derivatives of Formula I, wherein Ris a monocyclic carbocyclic aryl lower alkyl, such as, benzyl can beobtained from the same starting material, i.e., -chloro-2-pentanone,which is hereinafter described for preparing other derivatives ofFormula I. Thus, 5-chloro-2-pentanol is reacted with a benzyl halide,preferably the bromide in benzene solvent in the presence of base,suitably, sodium hydride. Analagous procedures to those hereinafterdescribed are then used to convert the thus ob tainedS-chloro-2-benzyloxy-pentane to the corresponding compounds ofFormula 1. Similarly, derivatives of Formula I wherein R is acyl can beobtained by methods described in the hereinafter attached subsection.Derivatives of Formula I wherein R is hydrogen can be obtained from thecorresponding compounds wherein R is acyl by base hydrolysis inaccordance with methods known to the art.

The utility of the 3-oxo-A-l9-nor-steroids of Formula VI, in addition tobeing hereinabove described, is also described in the aforesaid US.Patent and patent applications.

The following examples are intended to illustrate the invention and arenot to be construed to be limitative thereof. Temperatures are given inC.

EXAMPLE 1 (i) 6-( 3-Hydroxybutyl)-3aB-ethyl-3a-ethynyl-3-hydroxy-7-methoxy-imino-perhydro[ 3H ]benz[e]indane l.5 G. of (i)2-methyl-6a,B-ethyl-7a-ethynyl- 2,3,4,4b,5,6,6a,7,8,9a,9b,l0,1l-tetradecahydrocyclopenta[5,6]naphtho[2,l-blpyran-7-ol was dissolved inpyridine (5 ml.) containing water (0.25 ml.) and then treated withmethoxyamine hydrochloride (1 g). After standing at room temperature forhr. (one spot on tlc) the reaction was quenched with brine and 14 theorganicrnaterials were isolated with dichloromethane.

The organic extract was washed with water and taken to dryness in vacuoto yield the oxime ether (:)-6-(3-hydroxybutyl)-3aB-ethylJa-ethynyl-3-hydroxy-7- methoxyimino-perhydro[3H]benz[e]-indane as a solid. A sample of this material was crystallizedfrom isopropyl ether to yield pure material, m.p. l63-l65.

Anal. Calcd for C H NO C, 73,09; H, 9.76; N, 3.87. Found: C, 73.23; H,9.81; N, 3.8!.

EXAMPLE 2(i)-6-[3-0xo-butyl]-3a,fi-ethyl-7-methoxyimino-Baethynyl-3-hydroxy-perhydro[3H ]benz[e indane l G. of the crude alcohol-oxime ether, (i)-6(3-hydroxybutyl)-3aB-ethyl-3a-ethynyl-3-hydroxy-7-methoxyimino-perhydro[3H]benz[e]indane in dimethylformamide (DMF) (10ml.) was treated at 5 with a solution of chromium trioxide (l g.) in DMF(10 ml.) to which had been added concentrated sulphuric acid (.5 ml.)dissolved in DMF (3 ml.). The mixture was then warmed to roomtemperature and left to stir for l hr.

Dichloromethane and aqueous sodium bicarbonate solution were added. Theorganic phase was then washed with brine, aqueous sodium bisulphitesolution (10 ml; 2%), dried over MgSO, and taken to dryness in vacuo togive the ketone (i)-6-(3-oxo-butyl)-3a,Bethyl-7-methoxyimino-3a-ethynyl-3-hydroxy-perhydro[3H]benz[e]indane as aglass.

EXAMPLE 3 Mg.; of the glassy ketone purified by chromatography(i)-6-(3-oxo-butyl)-3a,B-ethyl-7methoxyiminc-3a-ethynyl3-hydroxyperhydro[3H}benz{e]indanewas dissolved in chloroform (5 ml) and treated with levulinic acid inhydrochloric acid (1N; 9:1; 5 ml) and left to stir at room temperaturefor 48 hr. (followed by tlc).

The mixture was quenched with dichloromethane and the organic phase waswashed with saturated aqueous sodium bicarbonate solution. Removal ofthe solvents in vacuo furnished the diketone (i)-6(3-oxobutyl)-3a,B-ethyl-3aethynyl-3-hydroxyperhydro[3H-]benz[e]indan-7-one as an oil. The use of pyruvic acid gave the sameresult.

This material failed to crystallize and appeared as one spot on tlc.

EXAMPLE 4 (t)-l 3B-Ethyl-l7a-ethynyl-17-hydroxy-gon-4-en- 3-one a. 128Mg. of the crude diketone,(:)-6-(3-oxobutyl)'3a,B-ethyl-3a-ethynyl-3-hydroxyperhydrol3H-)benz[e]indan-7-one in benzene (5 ml.) containing p-toluenesulphonicacid (25 mg.) was heated at reflux for 1 hr. (monitored by tlc).Dilution with more benacne and washing with aqueous sodium bicarbonatesolution (saturated) gave a semi-solid on removal of the solvents invacuo. Crystallization from dichloromethane/isopropyl ether mixtureyielded (i)-l3B-ethyll7oz-ethynyl-l7-hydroxy-gon-4-en-3-one as a solid,

15 mp. l9820l. Recrystallization from hexane/acetone mixture raised themelting point to 204-206.

b. The same material was prepared as follows: 430 mg. of the crudeoxidation product(i)-6-(3-oxobutyl)-3a,B-ethyl-7-methoxyimino-3a-ethynyl-3-hydroxyperhydro[3l-llbenzlelindane in methanol (15 ml.) was treated withaqueous hydrochloric acid (4N; 7.5 ml.) and heated at reflux for 2 hr.The products were isolated with dichloromethane to yield off-white solidwhich was chromatographed on silica gel (0.2-0.5 mm mesh; 80 ml).Elution with 5%, and ethyl acetate/benzene mixture gave one spotmaterial (by tlc) m.p. l85l95.

Crystallization from hexane/acetone gave (with mother liquor materials)pure (i)13B-ethyl-l7a-ethynyl-l 7hydroxy-gon-4-en-3-one.

EXAMPLE 5(:)-6-(3-Hydroxybutyl)-3a,B-methyl-3,7-dimethoxyimino-perhydro[3H]benz[e]indane747 Mg. of the enol ether, (i)-2-methyl-6a,B-methyl-2,3 ,4,4b,5,6,8,9,9a,9b, l 0,1l-dodecahydrocyclopenta(5,6)naphtho(2,l-b)pyran-7,(6aH)-one (a 1:1mixture of the possible isomers at C in pyridine (4 ml) was treated withwater (0.1 ml) and methoxyamine hydrochloride (500 mg.) and left tostand at room temperature for 48 hr. Dilution with dichloromethane andextraction with brine gave the dioxime (954 mg) on removal of thesolvent in vacuo.

Chromatography over silica gel (0.2-0.5 mesh; 50 g.) yielded the puredioxime on elution with 10% and 20% ethyl acetate/benzene mixtures. Thematerial failed to crystallize.

EXAMPLE 6 EXAMPLE 7 (i-)-19-Nor-androst-4-en-3 ,17-dione 107 Mg. of theketone (i)-6-(3-oxo-butyl)-3a,B-methyl-3,7-dimeth0xyimino-perhydro[3H]benz[e]indane in methanol (5 ml.)was treated with hydrochloric acid (6N; 1 ml.) and heated at reflux for2.5 hr. (followed by tlc). The mixture was cooled and worked up withdichloromethane and saturated aqueous sodium bicarbonate solution.Removal of the organic solvents in vacuo gave the crude material whichcrystallized from acetone/hexane to give (i)-l9-nor-androst-4-en-3,17-dione.

EXAMPLE 8 (i)-6-( 3-Hydroxybutyl )-3a,B-methyl-3B-hydroxy-7-methoxyimino-pe rhydro[ 3H ]benz[e]indane 837 Mg. of the enol ether,(i)-2-methyl6aB-methyl- 2,3,4,4b,5,6,6a,7,8,9,9a,9b,l0,1l-tetradecahydrocyclopenta(5,6)naphtho (2,1-b)pyran-7-B-ol (a 1:1mixture of isomers at C [i.e. prepared from the 1:1 mixture(i)-2-methyl-6aB-methyl- 2,3,4,4b,5,6,8,9,9a,9b,10,1l-dodecahydrocyclopenta(5,6)naphtho(2,1-b)pyran-7.(6aH)-one by lithiumaluminum hydride reduction]) was dissolved in pyridine (5 ml.)containing methoxyamine hydrochloride (500 mg.) and water (0.2 ml.).After standing at room temperature for 48 hr. (tlc indicated no changeafter 24 hr.) the products were isolated with dichloromethane and brine.Removal of the solvents in vacuo gave an oil which was chromatographedon silica gel (0.2-0.5 mm mesh; 60 g.). Elution with 30%-75% ethylacetate benzene mixtures yielded the diol, (i)-6-(3-Hydroxybutyl)-3a,,B-methyl-3B-hydroxy-7-methoxyimino-perhydro[3H]benz[e]indane,as a glass.

EXAMPLE 9 (i)- l 9-Nor-androst-4-en-3, l 7-dione 417 Mg. of the diol,(t)-6-(3-hydroxybutyl)-3a,B-methyl-3B-hydroxy-7-methoxyimino-perhydro[3H- ]benz[e1indane in DMF (5ml.) was treated with a mixture of chromium trioxide/sulphuric acid inDMF (500 mg/0.25m1/5.5 ml) and left to stand at room temperature for 2hr. (followed by tlc.) Dilution with water, saturated sodium bicarbonatesolution and extraction with dichloromethane gave the crude diketone asan oil. This material was dissolved in methanol (15 ml.) containinghydrochloric acid (4N; 7.5 ml) and heated at reflux for 2 hr. (tlcmonitoring). Dilution with brine and extraction with dichloromethanefurnished (:)-19- nor-androst-4-en-3,l7-dione as an oil.

Chromatography on silica gel (0.2-0.5 mm mesh; 50 m1) furnished one spotmaterial, m.p. l55 on elution with 10% and 20% ethyl acetate-benzenemixtures. Crystallization from dichloromethane-isopropyl ether mixturegave pure (:)-19-nor-androst-4-en-3,l7- dione, m.p. l55-l57.

EXAMPLE l0 25.4 G. of the triketoether,-)-trans-4-(3-oxo-tertiarybutoxy-octyl )-7a,]3-ethylperhydroindan-l,S-dione, was dissolved in tertiary butanol (70 ml.) and added to amixture of powdered sodium hydroxide (l g.) in tertiary butanol (250ml.) at 55 under nitrogen. After stirring at 55 for 1 hour, brine wasadded (1 liter) and the products were isolated with ether and worked upas usual to yield an oil (23.6 g.). Chromatography on alumina (2 kg.;grade "1, neutral; Woelm) gave the pure material(i)-6[3'tertiarybutoxybutyl]-3a,fl-ethyl- 1,2,4,5,8 ,9.9a,9b-octahydro-benz[e ]inden-3,(3aH )7- dione as a clear oil on elutionwith ether-pet.-ether 30-60 mixtures (15%25%). A sample was distilled togive a colorless oil; b.p. at. 0.5 mm (Kugal Rohr).

EXAMPLE 1 1 *-)-2 Methyl-6a,B-ethyl-2,3,4,6,8,9,9a,9b,10,1 1-decahydrocyclopenta [5 6] naphtho[2 1 -b] pyran-7 (6aH)-one 14.1 G. ofthe tricyclic material,(i)-6[3-tertiarybutoxybutyl]-3a,B-ethyl-4,5,8,9,9a,9b-hexahydro-1H-benz[e]inden-3,7-(2H,3aH)-dione, was dissolved in benzene, treatedwith p-toluenesulfonic acid (.6 g.) and heated under reflux for 4%hours. After cooling, the reaction mixture was worked up as usual togive the diene (i)-2-methyl-6a,,6-ethyl- 2,3,4,6,8,9,9a,9b,10,1l-decahydrocyclopenta[5,6- ]naphtho[2,1-b]pyran-7(6aH)-one, under N at 4in the dark. A sample crystallized twice from hexane had m.p. 1091l6.

EXAMPLE 12 (i)-6-( 3-Hydroxybutyl )-3a,B-methyl3.7-dimethoxyimino-perhydro [3H]benz[e]indane 980 Mg. of(i)-2-methyl-6a,B-methyl- 2,3,4 ,4b,5 ,6,8,9,9a,9b,10,1l-dodecahydrocyclopenta[5,6]-naphtho-[2,1-b]-pyran-7(6aH)-one in 5 ml ofpyridine containing 0.1 ml. water and 550 mg of hydroxylaminehydrochloride was kept at room temperature for 24 hours. Extraction withdichloromethane gave the (i)-6-(3-hydroxybutyl)-3a,B-methyl-3,7-dimethoxyimino-perhydro[3H]benz[e]indane oxime as an oil.

EXAMPLE 13 (:L)-6-( 3-Oxo-butyl )-3 a,B-methyl-3,7-dimethoxyimino-perhydro[ 3H ]benz[e]indane 700 Mg of(i)-6-(3-hydroxybutyl)-3a,B-methyl-3,7-dimethoxyimino-perhydro[3H]benz[e]indane was dissolved in benzenecontaining 4 ml. of methyl-ethylketone and 700 mg. of aluminumisopropoxide was heated at reflux for 24 hours. The reaction wasquenched with 50 ml. (2%) of aqueous caustic soda and the product,(i)-6-(3-oxo-buty1)-3a,B-methy1-3,7-dimethoxyimino-perhydro[3H]benz[elindane was isolated using methylenechloride.

EXAMPLE 14 (i)-6-( 3-Hydroxybutyl )-3a,B-ethyl-3a-ethynyl-3B-hydroxyperhydrol 3H]benz[e]indan-7-one-N,N-

dimethyl hydrazone 1 G. of (i)-2-methyl-6a,B-ethy1-ethynyl-2,3 ,4, 4b,5, 6, 6a, 7, 8, 9a, 9b, 10, 1l-tetradecahydrocyclopental[5,6]-naphtho-[2,l-b]pyran 7-01 in 5 m1. ofpyridine containing 0.1 ml. of water and 0.5 g. of N,N- dimethylhydrazine was left to stand at room temperature for 24 hours. Work up ofthe organic materials and isolation with dichloromethane yielded(t)-6-(3-hydroxybutyl)3a,B-ethyl-3a-ethynyl-3B-hydroxyperhydro[3H]benz[elindan-7-one-N,N-dimethylhydrazone.

EXAMPLE l5 (i)-3-(4-Tertiarybutoxypentyl)-6aB-methyl-1,2,3 5,6,6a-hexahydrocyclopenta[f] l benzopyran- 7 8H )-one(i)-2-(Z-Diethylaminoethyl)-6-(4-tertiarybutoxypentyl)tetrahydropyran-2-ol(28 g.) dissolved in xylene (140 ml.) was added to a mixture of2-methylcyclopentan-l,3-dione (13.7 g.), xylene (280 ml.) and aceticacid (140 ml.) and heated at reflux for 45 min.

The cold reaction mixture was washed with water, aqueous sodiumbicarbonate solution and dried over sodium sulphate.

Removal of the solvents and chromatography over alumina (870 g., grade111 neutral) yielded the pure above-titled dienol ether (22 g.) as anoil.

Calc. C, 76.27; H, 9.89; Found: C, 76.47; H, 10.03

The ultraviolet spectrum showed 11,, 253 mp. (e 17,700).

EXAMPLE 16 (i)-3-(4-Tertiarybutoxypentyl)-6aB-methy1- 1,2,3,5 ,6,6a,7,S-octahydrocyclopentalf] [l]benzopyran-7B-ol(i)-3-(4-Tertiarybutoxypentyl)-6aB-methyl- 1,2,3,5,6,6a-hexahydrocyclopenta[f] [l ]benzopyran- 7(8H)-one (23.1 g.)dissolved in tetrahydrofuran (464 ml.) was added to a slurry of lithiumaluminum hydride (4.6 g.) in tetrahydrofuran (232 m1.) at 10.

The mixture was then stirred a further 45 min. at 0 and treated withwater. The solids were filtered off and the solvents were removed toyield the alcohol (23.1

A sample of the titled product on crystallization from hexane had m.p.97-101.

Calc. C, 75.78; H, 10.41; Found: C, 76.01; H, 10.28 u.v. h 252mg (e18,700).

EXAMPLE 17 (i)-3 -(4-Tertiarybutoxypentyl )6aB-methyl- 1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f] [l]benzopyran-7B-ol (i)-3-(4-Tertiarybutoxypentyl )-6aB-methyl- 1,2,3,5 ,6,6a,7,8-octahydrocyclopenta[f] l lbenzopyran-7 -ol (22.5 g.) was dissolved intoluene (450 ml.) and treated with 5% palladium-on-carbon (3.4 g.) andhydrogenated at room temperature and pressure.

After the uptake of one mole of hydrogen, the solids were. filtered offand the solvents removed in vacuo to give the above-titled enol ether(23.1 g.) as a pale yellow oil.

A sample on chromatography over alumina (Neutral; grade 111) yieldedanalytical material showing no strong u.v. adsorbtion.

Calc. C, 75.38; H, 10.93; Found: C, 75.15; H, 10.93

LR. (chloroform) showed bands at 3625 (OH) and 1680 cm (enol ether).

EXAMPLE 18(i)-3-(4-Tertiarybutoxypentyl)-6aB-methyl-perhydrocyclopenta[f][l]benzopyran-4aJB-diol(i)-3-(4-Tertiarybutoxypenty1)-6aB-methyl- 1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f] [l]benzopyran-7B-ol (22.1 g.) inacetone (220 ml.) was treated with aqueous sulphuric acid (1N; 1 10 ml.)and left at room temperature for 3 hrs. Most of the acetone was removedin vacuo at 35 and the organic materials were isolated with ether.

Removal of the ether gave the above-titled hemiketal (21.5 g. as aglass).

A sample on chromatography over alumina (Neutral grade 111) yieldedmaterial showing bands in the infrared at 3625 cm (OH) and 1200 cm(O-t-butyl) and no enol ether bands.

EXAMPLE 19 (1')-Trans-4( 3 -oxo-7-tertiarybutoxy-octyl )-7a,B-methylperhydroindan-l ,S-dione (i)-3-(4-Tertiarybutoxypentyl)-6aBmethyl-perhydrocyclopentalf][l]benzopyran-4a,7B-diol (17.4 g.) dissolvedin acetone (700 ml.) was cooled to 15 and treated over 20 mins. with asolution of chromium trioxide (12.7 g.) dissolved in aqueous sulphuricacid (63.5 ml.)

After stirring a further 2 hrs. at room temperature, the products wereisolated from benzene to yield the above-titled triketone (15.4 g.) asan oil.

A sample on distillation (molecular still B.P. l95- 205 at .01 mm.)showed bands in the infra red spectrum at 1735 (cyclopentanone), 1708(cyclohexanone and alkyl ketone) and 1200 cm (O-bbutyl).

Calc. C, 72.49; H, 9.95; Found: C, 72.21; H. 10.00

EXAMPLE 20 (1-)-6-( 3-Tertiarybutoxybutyl )-3a,B-methyl-4,5,8,9,9a,9b-hexahydro-1-H-benz[e]inden-3 ,7-

(2H,3aH )-dione (i)-Trans-4-( 3-oxo-7-tertiarybutoxy-octyl )-7aB methylperhydroindan-l ,S-dione (13.8 g.) dissolved in tertiarybutyl alcohol(38 ml.) was added to a solution of sodium hydroxide (544 mg.) intertiary butyl alcohol (136 ml.) under nitrogen.

The mixture was stirred at 55 for 1 hr. hr., with acetic acid (1 ml.)and the organic materials were isolated with benzene.

Removal of the benzene in vacuo gave the abovetitled tricyclic material(11.9 g.) as a pale yellow oil.

The product showed strong absorbtion in the u.v. at A 247 mp. (e 13,000)and had the characteristic bands in the infrared spectrum at 1730(cyclopentanone) and 1660 and 1600 cm (cyclohexenone).

EXAMPLE 21 (i)-2-Methyl-6aB-methyl-2,3,4,4b,6,8,9,9a,9b,10,1 1-decahydrocyclopental 5 ,6]naphtho[2,1-b]pyran-7- (6aH)-one (i)-6-( 3-Tertiarybutoxybutyl )-3aB-methyl- 4,5,8,9,9a,9b-hexahydro-1H-benz[e]inden- 3,7(2H,3aH) dione g.) wasdissolved in benzene (300 ml.) containing p-toluene sulphonic acid (500mg.) and heated at reflux for 3% hrs.

The cold reaction mixture was washed with aqueous sodium bicarbonatesolution and the solvents were removed in vacuo to yield theabove-titled dienol ether (8 g.) as an oil showing bands in the infrared spectrum at 1735 (cyclopentanone) and 1645 cm (dienol ether).

The u.v. spectrum showed A 249 mp. (e 17,500).

EXAMPLE 22 (t)-2-Methyl'6a,8-methyl-2,3 ,4,5,6,8,9,9a,9b, 10,1l-dodecahydrocyclopenta[ 5 ,6]naphtho[ 2, 1 -b]pyran-7( 6aH )one(i)-2-Methyl-6aB-methyl-2,3,4,6,8,9,9a,9b,10.1 1-decahydrocyclopenta[5,6]naptho[2,1-b]pyran- 7(6aH)-one (8 g.) wasdissolved in toluene (200 ml.) containing triethylamine (1.5 ml.) and 5%palladiumon-carbon 1.5 g.) and hydrogenated at room temperature andpressure until one mole of hydrogen had been consumed.

The solids were filtered off and the solvents removed in vacuo to yieldthe abovetitled enol ether as an oil. Chromatography over alumina(Neutral; Grade 111) yielded pure product (6 g.).

Calc. C, 78.98; H, 9.42; Found: C, 78.79; H, 9.55

Infra red spectrum showed bands at 1740 (cyclopentanone) and 1680 cm(enol ether).

The same material was also prepared as follows: (i)- 6-(3-tertiarybutyoxybutyl )-3aB-methyl-4,5 ,8 ,9,9a,9bhexahydro-lH-benz[e]inden-3,7-(2H,3aH)-dione (1.5 g.) wasdissolved in ethanol (25 ml.) containing triethylamine (0.15 ml.) and 5%Pic. (200 mg.) and hydrogenated at room temperature and pressure untilno more hydrogen was consumed.

The solids were filtered off and the solvents were removed in vacuo toyield racemic6-(3)tertiarybutoxybutyl)-3afi-methylperhydro-benz[e]indane-3,7-dione asan oil.

This material showing infra red bands at 1735, 1705 and 1200 cm' wasdissolved in benzene (25 ml.) containing p-toluene sulphonic acid mg.)and heated at reflux for 4 hrs.

After washing the cold reaction mixture with brine and removal of thesolvents in vacuo, the residue was filtered through a column of alumina(Neutral; grade 111) to yield the above-titled pure enol ether.

EXAMPLE 23 (i)-2-Methyl-6aB-methyl- 2,3,4,4b,5,6,8,9,9a,9b,10,1l-dodecahydrocyclopenta[5,6]naphtho[2,1-b]pyran-7B-ol The enol etherZ-methyI-Gafi-methyl- 2,3,4,4b,5.6,8,9,9a,9b, 10,1l-dodecahydrocyclopenta[5,6]naphtho[2,1-b]pyran-7(6aH)one (3 g.) inether (20 ml.) was added to a slurry of lithium aluminum hydride (600mg.) in ether (25 ml.) at 10.

After stirring a further one hour at room temperature, water was addedand the solids were filtered off. Removal of the solvents yielded (3 g.)of a glass showing bands in the infra red at 3600 (OH) and 1680 cm"(enol ether).

EXAMPLE 24 (i)-l 3B-Ethyl-l7a-ethynyl-17-hydroxy-gon-4-en- 3-one Theproduct of Example 14 (i)-6-(3-hydroxybutyl)-3aB-ethyl-3a-ethynyl-3,6-hydroxyperhydrol3H-]benz[e]indan7-one-N,N-dimethylhydrazone was converted to theabove-titled compound via the intermediates(i-6-(3-oxo-butyl)-3a,B-ethyl-3a-ethynyl-S-hydroxyperhydro[3H]benz[e]-indan-7-one-N,N-dimethylhydrazone and(t)-6-(3-oxo-butyl)-3aB-ethyl-3aethynyl-3-hydroxyperhydro[3Hlbenzlelindan-7-one utilizing the procedures of Examples 2, 3 and 4.

EXAMPLE 25 (i)-2-Methyl-6aB-ethyl-2,3,4,4b,5,6,8,9,9a,9b,10,1 1-dodecahydrocyclopenta[5 ,6]naphtho[2,1-b]pyran- 7( 6aH )-one 33.3 G. ofthe crude dienol ether (i)-2-methyl-6aflethyl 2.3,4.6,8.9,9a.9b,10,1l-decahydrocyclopenta[5,6]naphtho[2,1-b]pyran-7(6aH)-one in toluene (300ml.) was treated with 5 g. of a carbompalladium catalyst andtriethylamine (2.5 ml.) and then hydrogenated at room temperature andpressure till no more hydrogen was consumed ("=28 liters; overnight).The

solids were filtered off and the solvents removed in We claim;

vacuo to give the product, (i)-2-methyl-6aB-ethyl- 1. Compounds of theformula 2,3,4,4b,5,6,8,9,9a,9b, l 0,ll-dodecahydrocyclopenta[5,6]naphtho[2,0-b]pyran-7(6aH)-one, as an oil. Z

This was a l:l mixture of C isomers. A sample crystal- R 5 (CH2 lizedtwice from hexane melted at l l l-l l5. Repeated m cyrstallizations fromhexane yielded the product enriched 85%) in one isomer, m.p. ll8-l22.

EX AM PLE 26 T (i)-2-Methyl-6aB-ethyl-7a-ethynyl- C2,3,4,4b,5,6,6a,7,8,9,9a,9b,l0, ll-tetradecahydrocyclopenta[5,6]naphthol[2,l -b]pyran-7-ol l5 Liquidammonia (600 ml.) was saturated with dry wherein Z CarbOnyL C NR or agroup of the acetylene (passed through a trap at -72) for 45 minformulautes and then treated with postassium metal (3 g.), with 1 continuousacetylene passage. This mixture was then stirred for a further 30minutes and then treated over R" 20 minutes with the crude enol ether(:t)-2-methyl- 6aB-ethyl-2,3,4,4b,5,6,8,9,9a,9b,l 0,1l-dodecahydrocyclopenta[5,6]naphtho[2,l-b]pyran-7(6aH)-one (8 g., m.p.ll8-l22)dissolved in dry tetrahydrofuran (120 ml.). The whole reactionmixture was then stirred 5 R is hydrogen or lower alkanoyl or monocyclicaroyl; R is hydrogen or lower aliphatic hydrocarbyl; m is an integerhaving a value of l or 2; R is lower for a further 2 hours. Ether (400ml.) was then added alkoxy hydmxy or a rad'cal of the formula and halfof the ammonia was allowed to distill off. Solid ammonium chloride (20g.) was then added followed by water (180 ml.) 15 minutes later. Theacetylene was disconnected and the products were worked up with ether inthe usual manner. Crystallization of the products from hexane yieldedpure (i)-2-methyl-6aB-ethyland Y are each mdepimdemly Ower alkyl 7aethyny| 2 3 4 4b 5 6 6a 7 8 R IS primary lower alkyl having from I to 5car bons; R is hydrogen or lower alkyl; R and R are each independentlyhyrogen or lower alkyl and T is carbonyl or a group of the formula 1 l-tetradodecahydrocyclopenta[ 5 ,6 lnaphthol 2 ,l blpyran-7-ol (5.8 g.),m.p. l38-l43.

Anal. Calcd. for C l-5 0,; C, 80.2]; H, 9.62; Found: H C, 80.l9;H,9.4840 I I i g; lf?g f 3300 (H C C 2. A compound as in claim 1, which is 1EXAMPLE 27 R Z\ a l 3-[3-Ethyl-gon-4-ene-3J 7-dione R1 5 2 The productof Example 25, (i)-2-methyl-6af3-ethyl- R 2,3,4,4b, S,6,8,9,9a,9b,l0,ll-dodecahydrocyclopenta[5,6]naphtho[2,l-b] pyran-7(6aH)-one wasconverted into the above-titled product by utilizing the 0 procedures ofExamples 5, 6 and 7 via the following CH2 intermediates:(i)-6-(3-hydroxybutyl)-3aB-ethyl-3,7-dimethoxyimino-perhydro[3l-l]benz[eindane and (i)- R6-(3-oxo-butyl)-3aB-ethyl-3,7-dimethoxyimino-perhydro[3H]benz[eindane. II

wherein R, R, R R, R, Z and m are as defined "1 -2, h h l 7 3. Acompound as in claim I, which is ,9a,9b,l-

Z\ 15 (CH2)m ll-tetradecahydrocyclopenta[5 ,6 ]naphtho[2,l -b]py- Rran-7-ol (i)'2-Methyl-6a,B-methyl- 2,3 ,4,4b,5,6,8,9,9a,9b,l0,l l-dodecahydrocyclopen- RN ta[5,6]naphtho[2,l-b]pyran-7(6aH)-one was con-CH verted to the above-titled compound by utilizing the procedure ofExample 26. R5

wherein R, R, R", R, R, Z and m are as defined in claim I. 4. A compoundas in claim 2 wherein R is methyl or ethyl; R and R are both hydrogen; Ris methyl; R is lower alkoxy; Z is a group of the formula R" ishydrogen; R is lower alkyl, lower alkenyl, or lower alkynyl and m is aninteger having a value of l.

5. A compound as in claim 3 wherein R is methyl or ethyl; R" and R areboth hydrogen; R is methyl; R is lower alkoxy; Z is a group of theformula R is hydrogen; R is lower alkyl, lower alkenyl or lower alkynyland m is an integer having a value of 6. process for preparing acompound of the formula wherein R is hydroxy, lower alkoxy or a radicalof the formula wherein X and Y are each independently lower alkyl; R ishydrogen or lower alkyl; R" and R are each independently hydrogen orlower alkyl; and m is selected from the group consisting of the partialformulas Yong,

wherein Z is carbonyl, C=NR or a group of the formula Z' is carbonyl ora group of the formula R is hydrogen or lower saturated aliphatichydrocarbyl; R is hydrogen or lower alkanoyl or monocyclic aroyl; R ishydrogen or lower aliphatic hydrocarbyl; m is an integer having a valueof l or 2; R is methyl or ethyl;

which comprises treating a compound of the formula wherein R R, R and Mare as defined above with the reagent or acid addition salt thereof ofthe formula NH,R

wherein R is defined as above, in an inert organic solvent, provided,however, that when an acid addition salt is used, the reaction is carried out in the presence of base.

7. A process as in claim 6 wherein R" and R are each hydrogen; R ismethyl and R is lower alkoxy and the reaction is carried out at atemperature of from 0 to 60C.

8. A process as in claim 6 wherein R is lower alkenyl or lower alkynyland R lower alkyl, is lower alkyl.

1. COMPOUNDS OF THE FORMULA
 2. A compound as in claim 1, which is
 3. Acompound as in claim 1, which is
 4. A compound as in claim 2 wherein R1is methyl or ethyl; R14 and R15 are both hydrogen; R5 is methyl; R islower alkoxy; Z is a group of the formula
 5. A compound as in claim 3wherein R1 is methyl or ethyl; R14 and R15 are both hydrogen; R5 ismethyl; R is lower alkoxy; Z is a group of the formula
 6. A process forpreparing a compound of the formula
 7. A process as in claim 6 whereinR14 and R15 are each hydrogen; R5 is methyl and R is lower alkoxy andthe reaction is carried out at a temperature of from 0* to 60*C.
 8. Aprocess as in claim 6 wherein R8 is lower alkyl, lower alkenyl or loweralkynyl and R8'' is lower alkyl.